Background
Germline mutations of the genes
BRCA1 (breast cancer 1, early onset) and
BRCA2 (breast cancer 2, early onset) are the most common cause of hereditary breast and ovarian cancer. Autosomal dominant mutations in
BRCA1/2 are associated with a lifetime risk of breast and ovarian cancer of up to 85% and 45% respectively [
1]. In addition, mutation carriers are at increased risk of several additional cancers including male breast cancer, pancreatic adenocarcinoma, prostate cancer, and melanoma [
2]. A recent publication has suggested
BRCA mutation carriers have an excess risk of mortality compared to non-carriers beyond that explained by the development or treatment of malignancy [
3]. Mai
et al. utilized a kin-cohort analysis to estimate the effect of
BRCA1/2 mutations on mortality. When deaths related to cancer diagnosis were excluded, the difference in life expectancy was 5.7 years lower for women and 3.7 years for men with mutations compared to age matched non-mutation carriers. The etiology of this excess mortality is currently unknown. However, BRCA1 and BRCA2 are members of a complex network of proteins involved in DNA repair and genomic stability [
4], suggesting their role could extend beyond regulation of neoplasia.
Recently, a cardiomyocyte specific
BRCA1 knockout mouse was developed, which showed increased susceptibility to myocardial ischemia and genotoxic agents (doxorubicin), suggesting BRCA dysfunction might play a role in cardiac damage during myocardial infarction and genotoxin induced cardiotoxicity [
5]. In a separate study, cardiomyocyte specific
BRCA2 knockout mice exhibited similar susceptibility to genotoxic agents [
6]. There was an association between increased double stranded DNA breaks and cardiac damage in both reports irrespective of the precipitating cause, alluding to the possibility of similarities in pathogenesis [
5,
6]. The idea of overlapping functions for BRCA1 and BRCA2 is further supported by evidence that the two proteins co-localize in the nucleus and play crucial roles in DNA repair [
4]. In addition, the cancer phenotypes expressed by germline mutations in both genes are similar [
7].
BRCA mutations that are associated with a markedly increased risk of cancer (most often resulting in protein truncation) are extremely rare in the general population [
8]. There are however, several hundred single nucleotide polymorphisms (SNPs) in
BRCA1/2, many of which are common [
9]. We hypothesized that common polymorphisms in
BRCA genes may be associated with cardiovascular disease (CVD), another complex trait, with molecular evidence (see above) suggesting a role for the
BRCA genes.
To test this hypothesis, we assessed the association between SNPs in
BRCA and CVD in individuals from the multi-ethnic SHARE and SHARE-AP studies [
10,
11]. These cross-sectional, randomly sampled, population-based studies explored differences in CVD risk factors and prevalence in South Asian, European, Chinese, and Aboriginal ethnic groups residing in Canada. The SHARE studies demonstrated that Aboriginal people and South Asians had the highest prevalence of CVD amongst the four ethnic groups [
10,
11].
Discussion
To our knowledge, this report is the first to suggest a possible association between variants in BRCA1/2 and CVD in human populations. However this observation requires confirmation, given that the effect size appears to be small, and our meta-analysis did not reach statistical significance. It is possible that the association we observed in the SHARE studies was due to chance alone, and is not a true association.
Very little has been published with respect to shared genetic predisposition to cancer and CVD. However, mechanistically, several common pathways are emerging. Most prominent in recent publications is the endothelin axis, with reports linking endothelin-1 to prostate cancer tumorigenesis [
25]. Additionally, animal models demonstrate upregulation of DNA repair mechanisms in heart failure induced by ischemic damage [
26]. As an example, topoisomerase-II-alpha, a protein involved in various aspects of DNA repair, is overexpressed in unstable plaque from human carotid atheromas [
27]. Given its integral role in genomic stability and DNA repair, a similar role in the pathogenesis of coronary atherosclerosis, plaque rupture, and response to ischemic damage may exist for
BRCA1/2. Finally, several SNPs associated with metabolic diseases, identified through genome wide association studies, have roles in cancer and chronic disease predisposition. For example, variants in
TCF7L2 predispose to both colon cancer and type 2 diabetes while variants in
HNF1B predisposes to type 2 diabetes and prostate cancer [
28].
Our study suggested a possible association between rs11571836 and rs1799943 and CVD in a multi-ethnic population. Analysis by ethnicity confirmed a statistically significant association with Aboriginal and South Asian ethnicities for rs11571836, while for rs1799943 the association was statistically significant only in the Aboriginal group. It is worth noting however, that with the exception of the Chinese group, all odds ratios trended in the same direction (ie. below 1) for both SNPs. This supports the possible explanation that the current analysis was underpowered to detect an association by individual ethnicity. In fact, only 17% and 6.9% of individuals with CVD in the study were European or Chinese respectively. Alternatively, lack of association between these SNPs and CVD in specific ethnicities may represent differences in LD in the region encompassing
BRCA2, as there are significant differences in LD structure in this region among ethnicities (Figure
1)
. In silico analysis of these two SNPs suggests both may modulate
BRCA2 transcript levels [
29], but there have been no published functional studies to date. Similarly, neither SNP has been definitively associated with breast cancer susceptibility. Thus, it is quite possible that rs11571836 and rs1799943 are not directly associated with CVD, but instead are in LD with other functional variants associated with CVD. Finally, there may be ethnic-specific differences in the pathogenesis of CVD such that
BRCA variation is only relevant to CVD in certain ethnicities, although this seems unlikely given the consistency of other risk factors for CVD across ethnicities [
15].
We were unable to demonstrate a statistically significant association between rs11571836 and incident MI in two large case controls studies of incident MI in South Asians, although a trend towards an association was present in INTERHEART. It is possible in INTERHEART that a larger sample size may have resulted in a statistically significant association, as the current sample size was underpowered (44% power) to detect a 15% risk reduction in MI risk for allele frequencies of 20%. A sample size of approximately 2600 cases and a similar number of controls is required to reach 80% power. Based on sample size, the PROMIS analysis was adequately powered, however, it is possible that utilizing imputation to infer the genotype of rs11571836 may have resulted in divergent results from what would have been observed had the SNP been directly genotyped. While the literature suggests good concordance between imputation and direct genotyping [
30], it is possible that the HapMap reference samples were not adequate for this region. Alternatively, subtle differences in LD patterns between South Asian populations could explain the lack of a reproducible association between rs11571836 and acute MI in the SHARE, INTERHEART and PROMIS studies. Conversely, the lack of replication would be anticipated if the association between
BRCA2 variants and CVD demonstrated in the SHARE studies occurred by chance. One means of further clarifying this possibility is to examine the association between
BRCA2 variants and CAD in published GWAS studies. There was no association between either rs11571836 or rs1799943 and CAD in the Wellcome Trust Case Control Consortium (WTCCC) GWAS study [
31]. However, the WTCCC study was composed exclusively of White Europeans, unlike our multi-ethnic or South Asian study populations. Unfortunately, lack of publically available data from addition multi-ethnic or South Asian GWAS studies limited our ability “look-up” these SNPs directly in additional studies.
Alternatively, variants in BRCA2 may be more relevant to the pathogenesis of other components of the composite CVD outcome utilized in SHARE (for example ischemic stroke), rather than acute MI. One significant limitation of utilizing the composite CVD outcome in genetic association studies is the heterogeneous pathogenesis of the outcomes studied. In the SHARE studies, the low number of events precluded an assessment of individual components of the composite CVD outcome. Testing the association between BRCA variants and measures of CVD other than MI, ideally from multiple ethnicities, could confirm or refute this hypothesis. In addition, experimental data has thus far only demonstrated a role for BRCA1 in the modulation of cardiomyocyte function following ischemic damage. Due to resource constraints, our analysis was limited to SNPs from BRCA2 that had been previously genotyped, however, investigating the role of SNPs in BRCA1 would be desirable. Finally, data from the murine knock-out models described earlier allude to the possibility that BRCA1/2 may play a greater role in modulating the severity of cardiomyocyte damage following an insult, rather than being directly implicated in initiation of cardiac injury. Therefore, testing the association between variants in the BRCA genes and the severity of a CVD outcome might prove more useful.
Competing interests
The authors declare no competing interests.
Authors' contributions
KZ was involved in conception of the study, data analysis, and drafting the manuscript. CX performed statistical analysis. RY was involved in genotyping and association analyses. MH performed statistical analysis. RM and ADD were involved in data acquisition and study co-ordination. GP, SYand JE were involved in study design, data acquisition, and aided in the drafting and revision of the manuscript. RAH, MBL, DS, and JD were involved in data acquisition, genotyping, and revisions of the manuscript. SSA was involved in conception of the study, data acquisition, statistical analysis, and drafting and revising the manuscript. All authors read and approved the final manuscript.